An essential role for nuclear receptors SXR/PXR in detoxification of cholestatic bile acids

TLDR

Hepatic hydroxylation is essential for bile acid metabolism and excretion, preventing cholestasis and liver damage. The study aims to determine whether the human xenobiotic receptor SXR and its rodent homolog PXR function as bile acid receptors. Using cultured cells and animal models, the authors demonstrate that SXR/PXR act as functional bile acid receptors. They show that lithocholic acid is a CYP3A substrate and that SXR/PXR activation induces CYP3A enzymes, providing resistance to LCA and other xenotoxicants, thereby establishing SXR/PXR as bile acid receptors that detoxify bile acids.

Abstract

Hepatic hydroxylation is an essential step in the metabolism and excretion of bile acids and is necessary to avoid pathologic conditions such as cholestasis and liver damage. In this report, we demonstrate that the human xenobiotic receptor SXR (steroid and xenobiotic receptor) and its rodent homolog PXR (pregnane X receptor) serve as functional bile acid receptors in both cultured cells and animals. In particular, the secondary bile acid derivative lithocholic acid (LCA) is highly hepatotoxic and, as we show here, a metabolic substrate for CYP3A hydroxylation. By using combinations of knockout and transgenic animals, we show that activation of SXR/PXR is necessary and sufficient to both induce CYP3A enzymes and confer resistance to toxicity by LCA, as well as other xenotoxicants such as tribromoethanol and zoxazolamine. Therefore, we establish SXR and PXR as bile acid receptors and a role for the xenobiotic response in the detoxification of bile acids.